Role of CDCP1 in the pathogenesis of autoimmune uveitis

CDCP1在自身免疫性葡萄膜炎发病机制中的作用

• 批准号: 10655755
• 负责人: FENG C LIN
• 金额: $ 50.4万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655755
• 关键词: Activated-Leukocyte Cell Adhesion Molecule; Active Immunization; Adoptive Transfer; Arrestins; Attenuated; Autoimmune Diseases; Biological Assay; Blindness; Blocking Antibodies; Blood-Retinal Barrier; CD6 antigen; Cell surface; Cytoskeleton; Data; Development; Disease; Endothelium; Epithelium; Event; Extracellular Domain; Flow Cytometry; Genetic; Human; Impairment; In Vitro; Infiltration; Interleukin-6; Knock-out; Knockout Mice; Knowledge; Ligands; Mediating; Monoclonal Antibodies; Mus; Myosin ATPase; Pathogenicity; Pathologic; Penetration; Permeability; Phosphorylation; Pre-Clinical Model; Process; Production; Proteins; Proteomics; Reagent; Reporting; Research; Retina; Role; Signal Transduction; Stress Fibers; Structure of retinal pigment epithelium; Surface; Surface Plasmon Resonance; T cell infiltration; T cell regulation; T cell response; T-Cell Activation; T-Lymphocyte; TFRC gene; Testing; Therapeutic Uses; Therapeutic antibodies; Tight Junctions; Treatment Efficacy; Uveitis; Work; autoimmune pathogenesis; autoimmune uveitis; cell motility; conditional knockout; cytokine; efficacy evaluation; extracellular; immunogenicity; immunoregulation; in vivo; inhibiting antibody; insight; knock-down; migration; mutant; nanobodies; new therapeutic target; next generation; novel; novel therapeutic intervention; protein protein interaction; receptor; selective expression; targeted treatment; therapeutic target

ABSTRACT Autoimmune uveitis is a major cause of blindness for which no cure and limited treatment options are available. We found that CUB domain-containing protein 1 (CDCP1) knockout (KO) mice are protected from experimental autoimmune uveitis (EAU) induced by adoptive transfer of pre-activated uveitogenic T cells, suggesting that CDCP1 facilitates pathogenic T cell infiltration through the blood–retina barrier (BRB) to induce EAU. In pilot mechanistic studies, we discovered that CDCP1 is selectively expressed on retinal pigmented epithelial cells (RPEs) in the retina and identified CD71, an established T cell activation marker, as a new ligand of CDCP1 in addition to CD6, another T cell marker. Stimulation with CD6 or CD71 induced CDCP1-mediated RPE cytoskeletal remodeling, a process known to impair epithelial barrier functions, and increased RPE production of IL-6, a pathogenic cytokine known to disrupt the endothelial barrier integrity. These intriguing data provide strong evidence in support of CDCP1 as a novel immunoregulator that interacts with CD6 and CD71 on T cells to facilitate pathogenic T cell infiltration through the BRB to induce EAU. Further, our data suggest that CDCP1 could be targeted for treating autoimmune uveitis. In this proposed study, we aim to use the unique reagents that we have developed or obtained in our preliminary studies to elucidate the detailed mechanisms by which CDCP1 regulates both the outer and inner BRB to facilitate T cell infiltration into the retina, and to determine the potential of CDCP1-targeted therapeutics using various conditional KO mice and our already developed anti-CDCP1 monoclonal antibodies and nanobodies. The proposed work should provide novel insights into our understanding of the pathogenesis of autoimmune uveitis and open new avenues of research in which CDCP1 is explored as a key immunoregulator and new therapeutic target for this blinding disease.

摘要 自身免疫性葡萄膜炎是致盲的主要原因，目前尚无治愈方法和有限的治疗选择。 可用。我们发现幼体结构域包含蛋白1(CDCP1)基因敲除(KO)的小鼠受到保护 过继转移预活化葡萄膜生成T细胞诱导的实验性自身免疫性葡萄膜炎(EAU) 提示CDCP1促进致病T细胞通过血视网膜屏障(BRB)的侵袭 真的。在初步的机制研究中，我们发现CDCP1选择性地在视网膜色素沉着处表达 视网膜中的上皮细胞(RPEs)，并确定CD71是一种新的配体，CD71是一个已建立的T细胞激活标记 CDCP1是除CD6外的另一种T细胞标志物。CD6或CD71刺激诱导CDCP1介导 RPE细胞骨架重构，这是一个已知的损害上皮屏障功能的过程，并增加了RPE 产生IL-6，一种已知破坏内皮屏障完整性的致病细胞因子。这些引人入胜的数据 提供强有力的证据支持CDCP1作为一种新的免疫调节剂与CD6和CD71相互作用 T细胞促进致病T细胞通过BRB的侵袭诱导EAU。此外，我们的数据表明， CDCP1可作为治疗自身免疫性葡萄膜炎的靶点。在这项拟议的研究中，我们的目标是使用独特的 我们在初步研究中开发或获得的试剂，通过以下方式阐明详细的机制 CDCP1同时调节外BRB和内BRB，以促进T细胞进入视网膜，并 利用各种条件性KO小鼠和OUR已经确定CDCP1靶向治疗的可能性 开发了抗CDCP1的单抗和纳米抗体。拟议的工作应该提供新颖的 深入了解自身免疫性葡萄膜炎的发病机制并开辟新的研究途径 其中CDCP1被探索为一种关键的免疫调节剂和治疗这种致盲疾病的新靶点。